Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown that 3F8, a murine IgG3, monoclonal antibody (MoAb) specific for the ganglioside GD2, mediates tumor cell kill in vitro and in vivo. We now describe receptor requirements of polymorphonuclear leukocytes (PMN) in 3F8-mediated cytotoxicity (ADCC) of human GD2 (+) melanoma and neuroblastoma cell lines. PMN from a child with leukocyte adhesion deficiency (LAD) were devoid of CD11/CD18 adhesion molecules and mounted no detectable ADCC. MoAb to CD11b, CD11c, and CD18 each efficiently blocked ADCC by normal PMN. In contrast, a panel of different MoAbs to CD11a had no significant inhibitory effect on ADCC, a finding consistent with the low-to-absent expression of the CD11a ligand, intercellular adhesion molecule-1, on the target cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) significantly increased the expression of CD11b, CD11c, and CD18 on normal PMN, decreased the expression of Fc receptors (FcR), and enhanced ADCC by normal but not by LAD PMN. MoAbs to FcRII and FcRIII each efficiently blocked ADCC; anti-FcRI MoAb had no effect. Flow cytometry using anti-FcRII MoAb versus anti-FcRIII MoAb did not show cross competition, suggesting that inhibition of ADCC was not a steric effect resulting from FcRII proximity to FcRIII. PMN deficient in FcRIII (obtained from patients with paroxysmal nocturnal hemoglobinuria) and PMN depleted of FcRIII by treatment with elastase or phosphatidylinositol (PI)-specific phospholipase C produced low ADCC, supporting a role for the PI-liked FcRIII. Thus, optimal ADCC using human PMN, human solid tumor cells, and a clinically active MoAb (conditions that contrast with the heterologous antibodies and nonhuman or nonneoplastic targets used in most models of PMN ADCC) required CD11b, CD11c, FcRII, and the PI-linked FcRIII. Furthermore, in this clinically relevant system, GM-CSF enhancement of antitumor PMN ADCC correlated with increased expression of CD11/CD18 molecules.
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PMID:Absolute requirement of CD11/CD18 adhesion molecules, FcRII and the phosphatidylinositol-linked FcRIII for monoclonal antibody-mediated neutrophil antihuman tumor cytotoxicity. 134 7

Fc gamma RIIA (CD32), a conventional type I transmembrane protein, and Fc gamma RIIIB (CD16B), which has a glycan phosphatidylinositol (GPI) membrane anchor, are both expressed on human neutrophils. Although some details remain to be elucidated, signaling following crosslinking of Fc gamma RIIA requires the activation of tyrosine kinases of both Src-family kinases and Syk, resulting in tyrosine phosphorylation of Shc, phospholipase C gamma isozymes, and a [Ca2+]i transient. Ligation of neutrophil Fc gamma RIIIB triggers a [Ca2+]i transient, and degranulation, although probably not ADCC or an oxidative burst. However, the mechanism for signal transduction by Fc gamma RIIIB, which lacks a transmembrane domain, is not known. Fc gamma RIIA and Fc gamma RIIIB appear to synergize with each other, leading to suggestions that the GPI-anchored Fc gamma RIIIB utilizes the Fc gamma RIIA signaling apparatus. The relevance of proposed specialized membrane domains enriched in GPI-anchored proteins, sphingomyelin and glycolipids to the signaling properties of Fc gamma RIIIB likewise remains to be explored.
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PMID:Function of human Fc gamma RIIA and Fc gamma RIIIB. 761 94